Mifamurtide (MTP-PE)

What is it?

Mifamurtide is the brand name for muramyl tripeptide phosphatidylethanolamine or MTP-PE for short. It is a synthetic derivative of muramyl dipeptide (MDP), which is an immune-stimulatory component of the bacterial cell wall. It’s advantage is that it has a longer half-life in plasma than MDP.

Mifamurtide is licensed for use as an adjunct in the treatment of high-grade resectable non- metastatic osteosarcoma after macroscopically complete surgical resection in children, adolescents and young adults. There has been much debate over the evidence to support it’s use but after much deliberation the National Institute for Health and Clinical Excellence (NICE) granted permission for it’s use in the UK in October 2011.  Read more about the NICE guidance.

How does it work?

Nucleotide-binding oligomerization domain-containing protein 2, or NOD2 for short, is a receptor found in monocytes and macrophages, which recognises bacterial peptidoglycan, stimulating an immune response. MTP-PE is recognised by NOD2 and thus simulates a bacterial infection, inducing an immune response and a cascade of cytokines including Tumour Necrosis Factor alpha (TNFα), which in turn generates a macrophage-mediated attack on the cancer cells.

The use of an immune stimulant like MTP-PE makes intuitive sense in the treatment of osteosarcoma, as post-resection infection has been shown to increase overall survival. Read more about infection in osteosarcoma.

The Evidence

There is one randomised controlled trial looking at the effect of Mifamurtide as an adjunct in the treatment of osteosarcoma. Meyers et al and the Children’s Oncology Group published the trial of 662 young people with localised, resectable osteosarcoma. They were randomly assigned to high-dose methotrexate, cisplatin, and doxorubicin plus or minus ifosfamide in a 2×2 factorial design, which also included a randomised evaluation of MTP. The study concluded that the addition of MTP to chemotherapy improved 6-year overall survival from 70% to 78% (P=0.03). The study has however generated much controversy. Read the paper for yourself in the Journal of Clinical Oncology.

Critics of the paper cite differences in the chemotherapy regimes in the different arms of the study, with cisplatin omitted from pre-operative chemotherapy in the ifosfamide-containing arm. Questions have also been raised about the apparent lack of effect of MTP on event-free survival (EFS) while at the same time overall survival (OS) is improved, as other studies suggest that EFS and OS are inextricably linked.

In defence of the paper it is pointed out that the trial was only powered to show a difference in effect from the MTP, which it does when the addition of MTP is looked at in isolation. It is also pointed out that MTP-containing arms of the trial had worse tumour necrosis at the time of resection, normally associated with a poorer prognosis, and yet those patients had the reported improvement in survival despite this.

You can read an eloquent commentary on some of the controversies in the Journal of Clinical Oncology.

You can read a riposte from the authors of the RCT of MTP, also in the Journal of Clinical Oncology.

  1. Meyers PA, Schwartz CL, Krailo MD, et al: Osteosarcoma: The addition of muramyl tripeptide to chemotherapy improves overall survival—A report from the Children’s Oncology Group. J Clin Oncol 26:633-638, 2008
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The Cade Regime for Osteosarcoma

Sir Stanford Cade was one of the pioneers of radiotherapy and worked at the Westminster Hospital between 1924 and 1960. Amongst his extraordinary output he published a thoughtful paper on the treatment of osteogenic sarcoma in the prechemotherapy era (1).  He reasoned that early amputation had no impact on survival in osteosarcoma, and therefore that early metastasis was the norm. Furthermore he argued that to amputate the limbs of patients with such a poor prognosis was unreasonable and mutilating. The Cade regime therefore involved high dose radiotherapy to the primary tumour site, followed by secondary amputation if the patient survived long enough. He was able to demonstrate clinical, radiological and pathological responses to radiotherapy in this relatively radioresistant tumour.  His description defined treatment for osteosarcoma in the prechemotherapy era.

Reference:

Journal of the Royal College of Surgeons of Edinburgh. 1955 Dec ;1(2):79–111.

Osteosarcoma

An osteosarcoma is a malignant tumour containing cells of mesenchymal origin and which is characterised by the formation of malignant osteoid.  Osteosarcomas are the most common primary bone sarcoma, but osteosarcomas also (rarely) occur in bone – in other words the prefix “osteo-” relates to the production of osteoid matrix rather than an origin in bone.

  • Incidence is around 1-2 per million per annum, which is around 131 new cases in England per annum
  • Osteosarcomas have a peak incidence in the second decade of life, and a smaller peak in the elderly
  • They classically occur in the metaphyseal regions of long bones  where most growth occurs (ie distal femur, proximal tibia, proximal humerus)
The WHO histological classification of osteosarcoma recognises the following groups:
1. Central (Medullary) tumours
  • conventional central osteosarcomas (the most common type)
  • telangiectatic osteosarcoma
  • intraosseous well-differentiated (low-grade) osteosarcomas
  • small-cell osteosarcomas
2. Surface (peripheral) tumours
  • parosteal (juxtacortical) well-differentiated (low-grade) osteosarcomas
  • periosteal osteosarcoma: low to intermediate-grade osteosarcoma
  • high-grade surface osteosarcoma

References:

Bone Sarcomas: incidence and survival rates in England – NCIN Data Briefing. National Cancer Intelligence Network 2010.